Plasmodium malaria remains a tremendous public health burden. In order to sustain recent progress in decreasing malaria related morbidity and mortality further progress in understanding antimalarial mechanism of action and resistance is required. In order to achieve this high-throughput single agent and combination screening technology will be utilized to chemogenomic profiling of P. falciparum drug responses. This information will then be analyzed to identify differential drug responses and the underlying candidate genetic loci that will be further tested using recently developed genetic tools for P. falciparum. In addition, potent small molecules from our drug collection libraries, including the Mechanism Interrogation PlatE (MIPE) library, will be further evaluated for development of lead compounds for antimalarial combination therapies. Compound libraries will be screened against standard laboratory lines and lines with distinct resistance phenotypes. The information will permit the identification of developmental candidates that remain potent against parasites resistant to current utilized antimalarials.